Severe loss of vision occurs due to age-related macular degeneration (AMD) and approximately 11 million people in the US have some form of AMD which is expected to double by 2050. Most of the current clinical treatments are primarily focused on slowing down the progression of the disease, as there is neither a cure that can stop the degeneration nor a therapy, other than retinal prostheses, that can restore vision lost due to the degeneration. Current systems, however, are limited by poor resolution (higher electrode density requiring more current, leading to heat production), retinal damage over a time period and cellular overgrowth due to surgical implantation. Use of optogenetic sensitization of retinal cells has several advantages over electrical stimulation such as single-cell resolution, cellular specificity and minimal-invasiveness. However, clinical translation of optogenetic enabled vision restoration suffers from the drawback of active stimulation by blue light source having intensity order of magnitude higher than ambient light owing to the narrow spectral sensitivity of single opsins. To allow ambient-light based stimulation, we propose to utilize (via intravitreal injection lenti-viral vector carrying multi- color opsins (VMCO) to sensitize retinal ganglion cells in photodegenerated AMD retina to different colors of light, allowing broad spectral excitability and thus, significantly higher sensitivity to ambient light. The overall objective of this Phase I SBIR project is to demonstrate behavioral restoration of vision in mice models of late-stage AMD with ambient-level white-light stimulation of retinal ganglion cells (RGCs), sensitized by VMCO. Towards this goal we have following aims: (i) Evaluation of long-term viability and functioning of virally-delivered multi-color opsin sensitized degenerated-retina of AMD mice model; and (ii) Behavioral restoration of vision in mice models of late stage AMD after multi-color opsin sensitization of the degenerated-retina. This proposal is a collaborative effort between NanoScope Technologies, Retina Foundation, and Drs. Mohanty and Kim's laboratories at University of Texas. Success of this proposal will lead to a new clinical approach for treating patients with AMD by conventional intravitreal injection of virus carrying opsin constructs. We believe that such treatment will lead to restoration of high-resolution vision in AMD patients by white-light stimulation of multi-color opsin sensitized RGCs at ambient light level. Upon completion of the Phase I we envision a Phase II SBIR targeted at (i) optimizing the final product design and method, (ii) identifying AMD-population for treatment, (iii) submission of orphan drug license application to FDA, and (iv) providing core marketing material for commercializing the product and method.